The invention relates to novel ergoline amine derivatives with an antihypertensive effect, in particular for use in medicine.
About 10 million people in Germany alone suffer from high blood pressure [E. Kxc3x6nig, Bluthochdruck, Erste Warnsignale, Gefahren und Behandlung, Wort and Bild Verlag Konradshxc3x6he, GmbH and Co. Baierbrunn, 1995]. There is still a pressing need for novel agents with novel principles of action, in particular without the unwanted side effects frequently occurring with the known products, for treating this disease, which is regarded as a major risk factor for various cardiovascular disorders such as arteriosclerosis, myocardial infarction, stroke and kidney damage.
The ergoline amine derivatives previously disclosed and described in the literature mainly have antisecretory and antiulcer effects. Also known from this class of substances are stimulators of the central nervous system and ergoline thiourea derivatives with antiparkinson activity. Other ergoline derivatives show antiprolactin activity, serotonin antagonistic effects, sympatholytic and oxytocin-like activity. In the search for novel antihypertensives, among the ergot alkaloids which mostly have pressor activity also a few 8xcex2-aminomethylergoline derivatives with an antihypertensive effect have been found, with urea and thiourea derivatives [A. Temperilli, D. Ruggieri, P. Salvati, Eur. J. Med. Chem., 1988, 23, 77.] or organometallic derivatives of 8xcex2-aminomethylergoline acting as structural elements. It is known that a number of unwanted side effects occur after use of antihypertensives such as, for example, clonidine, reserpine, nifedipine, dihydralazine, and known urea and thiourea derivatives of 8xcex2-aminomethylergoline, especially nausea, diarrhea, fatigue, depression and edema.
Overall, it is estimated that known drugs with antihypertensive activity do not meet the requirements for adequate hypotensive activity and good tolerability, which makes it necessary to look for novel compounds, especially with novel mechanisms of action.
The invention is based on the object of providing suitable, readily soluble, selectively acting and well tolerated drugs which have high antihypertensive activity after enteral and parenteral administration. The compounds are intended to make effective treatment of hypertensive diseases possible and to be better tolerated than therapeutic agents used to date.
The object is achieved according to the invention by providing novel 8xcex2-aminomethylergoline derivatives which comprise a diamine structural unit coupled via a dicarboxylic acid. It has been found, surprisingly, that 8xcex2-aminomethylergoline derivatives which are linked via the aminomethyl group by means of a dicarboxylic acid to a diamine have a pronounced antihypertensive effect, with both the extent of the lowering of blood pressure and the duration of the pharmacological effect being controlled via the diamine/dicarboxylic acid combination, structure-activity relations being derivable. Novel principles of action arise from the molecular structures of the introduced side chain, which differs greatly from conventional peptides.
The tested compounds show on intravenous and enteral (intraduodenal) administration of 0.1 to 5 mg/kg of body weight to anesthetized rats a dose-dependent and persistent, large hypotensive effect and show on isolated vessels a high selectivity on the xcex11 receptor.
The hypotensive effect of the compounds of the invention is not caused by an effect on the central nervous system.
Substances in therapeutic use, such as minoxidil and dihydroergocornine, are exceeded in their effect many times by the substances of the invention. The unwanted side effects frequently observed with lysergic acid derivatives can be avoided by very much lower active doses.
The aminoergoline derivatives of the invention have the general formula 1: 
in which
R5=H, alkyl, aryl, acyl, CN;
R6=H, alkyl, halogen;
R7, R8=H or together a bond;
R1 together with the two adjacent N atoms is the residue of a diamine,
R4 together with the two adjacent carbonyl groups is the residue of a dicarboxylic acid,
R2 is H, acyl and R3 is H, or
R2 and R3 together are a divalent radical R1, and salts, in particular pharmaceutically usable salts, of these compounds.
R1 and R4 have the following meanings in particular:
a) R1 and R4 are, independently of one another, C1-C10-alkylene, branched or unbranched, which is optionally interrupted by O, S, NR9, arylene, heteroarylene, cycloalkylene, heterocycloalkylene and/or optionally substituted by R10,
R9=alkyl, benzyl, aryl, acyl,
R10=R9, also halogen, OH, SH, NO2, CN;
b) R1 and R4 are, independently of one another, C1-C10-alkylene, branched or unbranched, which comprises one or more isolated and conjugated double bonds and is optionally substituted by R10, and/or is optionally interrupted by O, S, NH, NR9, arylene, heteroarylene, cycloalkylene, heterocycloalkylene;
c) R1 and R4 are, independently of one another, cycloalkylene or heterocycloalkylene with 3-8 ring members or such cycles with, optionally, 1-2 bridges with in each case 1-3 chain members, which comprise C, O, NH, NR9, S, and arylene or heteroarylene with 5-7 ring members, which are optionally substituted by R10;
d) R1 and R4 are, independently of one another, two cycloalkylenes linked by R11 and optionally interrupted in the ring by O, S, NH, NR9 and/or optionally substituted by R10, O or S;
R11 alkylene, O, S, S2, NR9.
R4 can moreover have the following meanings:
a) R4 is two arylene or heteroarylene radicals linked by R12;
R12=alkylene, Fe, O, S, S2, NR9 
b) R4 is porphyrindiyl, optionally substituted one or more times by alkyl, unsaturated one or more times, having central atoms such as, for example, Zn, Ca, Mg and Fe, where a residual charge occurring after the complexation is neutralized by an anion of a pharmaceutically acceptable acid.
Salts of compounds of the formula 1 are, in particular, pharmaceutically acceptable salts and may have been produced by quaternization, either by reacting the product with conventional alkylating agents or by using building blocks which have already been quaternized. Salts of the invention are also those produced by protonation of compounds of the formula 1 by reaction with monobasic to tribasic acids with a maximum charge corresponding to the number of protonatable positions, in most cases the number of implemented nitrogen atoms. Acids which can be used in this connection are inorganic acids such as, for example, hydrohalic acids, sulfuric acid and phosphoric acid, and the amides thereof, or other pharmacologically suitable derivatives. The organic acids may be, for example, carboxylic, sulfo or sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid.
Preference is given to the following compounds of the formula 1, in which
R2, R3, R6, R7, R8 are H; R5 is CH3,
R1 and R2 are, independently of one another, five- to eight-membered cycloalkyl or heterocycloalkyl, optionally unsaturated one or more times, or are aryl and heteroaryl consisting of one or two rings with a ring size of 5 to 7 members. Said cycles can optionally be substituted by halogen, nitro, amino or alkyl-substituted amino, alkoxy, OH, SH, O and S. The heterocycles mentioned can comprise one or more heteroatoms, in particular N, O or S. It is also possible for R1 and R4 to be C2-C8-alkylene which can optionally be interrupted by one to three, preferably one, 5-7-membered saturated, or unsaturated one or more times, cycles, heterocycles, and aryls or heteroaryls, and the heteroatoms in these cases may be oxygen, sulfur, nitrogen or R9-substituted nitrogen.
Compounds of the formula 1 in which R2, R3, R6, R7, R8 are H, R5 is CH3 are depicted in particular in the following table.
The meanings applying in the foregoing description are as follows:
alkyl/ene is (also in composite meanings such as alkoxy, alkoxycarbonyl, etc.) in particular C1-C5-alkyl/ene, and C1-C5-alkyl/ene which is substituted by xe2x80x94CN, xe2x80x94NO2, dialkylamine, halogen, OH, SH, xe2x80x94O-alkyl (alkoxy), xe2x80x94CONH2 or alkoxycarbonyl, optionally unsaturated one or more times.
Cycloalkyl/ene is, in particular, C3-C8-cycloalkyl/ene, and cycloalkyl/ene which is substituted by CN, NO2, dialkylamine, halogen, OH, SH, alkoxy, CONH2 or alkoxycarbonyl, optionally unsaturated one or more times.
Aryl/ene is, for example, a five- o r six-membered aromatic system, mainly cyclopentadienide, phenyl/ene or halogen-, OHxe2x80x94, SHxe2x80x94, alkoxy-, NO2xe2x80x94, CNxe2x80x94 or alkyl-substituted phenyl/ene.
Heteroaryl/ene is, for example, a six-membered aromatic system which comprises one to three nitrogen atoms or a five-membered aromatic system which comprises one nitrogen, oxygen or sulfur atom, optionally substituted by halogen, OH, SH, alkoxy, NO2, CN or alkyl.
Aryl/ene and heteroaryl/ene are also polyaromatic or fused aromatic systems consisting of 2-8 five- to seven-membered rings, optionally substituted by halogen, OH, SH, alkoxy, NO2, CN or alkyl.
Heterocycloalkyl/ene is, for example, 3-8-membered cycloalkyl/ene which comprises nitrogen, oxygen or sulfur as heteroatom, but is also a polycyclic ring system consisting of 2-4 rings which comprises at least one heteroatom from the group of nitrogen, oxygen or sulfur, optionally substituted by halogen, OH, SH, alkoxy, NO2, CN or alkyl.
Acyl is, for example, C1-5-alkanoyl which is optionally substituted by halogen, alkyl, cycloalkyl or aryl. Acyl is preferably acetate and trifluoroacetate.
Halogen is the residue of a hydrohalic acid and is, in particular, fluorine, chlorine, bromine or iodine.
Alkanoyloxy is, in particular, the radical of an optionally halogen-, OHxe2x80x94, SH-substituted C1-5-alkanoic acid, in particular CH3COO and CF3COO.
The radicals R on asymmetric centers in compounds of the formula 1 may be in the xcex1 or xcex2 position. Accordingly, the invention encompasses both the pure diastereomers and the corresponding mixtures of diastereomers.
The compounds of the invention are prepared, for example, by, in a manner known per se,
a) linking a diamine in a suitable solvent such as, for example, CH2Cl2 to the solid phase such as, for example, chlorotrityl-resin, in the presence of a base such as, for example, diethylisopropylamine;
b) coupling a dicarboxylic acid or a dicarboxylic anhydride to the amine described under a), in a suitable solvent, such as, for example, a CH2Cl2/N-methylpyrrolidone (NMP) mixture (1:1), in the presence of suitable coupling reagents such as, for example, hydroxybenzotriazole (HOBt) and diisopropylcarbodiimide (DIC);
c) coupling a suitable ergoline derivative such as, for example, 8xcex2-aminomethyl-6-methylergoline, in a suitable solvent such as, for example, NMP, in the presence of suitable coupling reagents such as, for example, HOBt and DIC, to the resin loaded as under b);
d) cleaving the substance prepared under c) off the support material with suitable, acids such as, for example, trifluoroacetic acid (TFA), resulting in compounds of the formula 1 as salts of trifluoroacetic acid;
e) converting the substance obtained as under d) with suitable bases such as, for example, K2CO3 into the free amine;
f) reacting the derivatives prepared in e) with acids such as, for example, HCl, acetic acid or ammonium salts such as, for example, NH4Cl and with alkyl and benzyl halides, such as, for example, MeI, PhCH2Br, to give the corresponding ammonium salts, resulting in compounds of the formula 1 as ammonium salts or quaternized amino compounds;
g) reacting the derivatives prepared in e) with acylating agents such as, for example, acetic anhydride, in the presence of basic solvents such as, for example, pyridine, to give the corresponding acylamido derivatives, resulting in compounds of the formula 1 in which R2 is acyl.
The antihypertensive effect was demonstrated in animal experiments with invasive measurement of blood pressure. For this purpose, the substances were administered intravenously and enterally (intraduodenally) to anesthetized rabbits and rats. Dose-dependent falls in blood pressure were observed thereafter, with no adverse effect on the heart rate. There is only an inconsiderable difference in the maximum strength of action after 0.5 mg/kg i.v. or 5 mg/kg i.d., which suggests rapid and complete enteral absorption. The results for selected compounds are compiled in Tables 1 and 2.
The compounds of the formula 1 are suitable on the basis of their antihypertensive activity for use in human medicine as pharmaceuticals for hypertensive diseases or diseases whose symptoms are caused by elevated blood pressure.
The ergoline derivatives of the invention can be used either alone or in combination with other commercially available and novel cardiovascular agents for potentiating the activity of these compounds, which makes it possible to reduce side effects by decreasing the dosages to be employed. The ergoline derivatives can be used either alone or in the form of pharmaceutical products with physiologically tolerated excipients and carriers known from the prior art for said diseases, or conventional pharmacological use forms, such as enteral or parenteral administration, being possible in principle.